This project is concerned with cardiac membrane currents and their regulation by key drugs such as catecholamines, digitalis and local anesthetics. Experimental and theoretical work will develop an improved system for measuring membrane currents, using rabbit Purkinje strands and a modified three-microelectrode voltage clamp. The method will avoid many difficulties with previous approaches, and allow the study of regenerative inward currents. A set of experimental criteria will be used to check the validity of the measurements. We will characterize the slow inward current and its role in (a) slowly rising, Ca-dependent action potentials, and (b) repetitive activity in partially depolarized tissue. The sensitivity of the slow inward current to catecholamines will be determined and related to the positive inotropic effect. Appropriate refinements of the technique will hopefully allow the study of the rapid excitatory sodium current, its inhibition by tetrodotoxin and local anesthetics, and the influence of membrane potential and prior activity on the drug effects. We will study the mechanism of action of local anesthetics in preventing arrhythmogenic spontaneous impulses in specialized conducting tissue under digitalis intoxication.